The End of the Age of Incrementalism

RNAi Therapeutics aims at addressing high unmet medical need at its genetic root. It is not about dressing existing drugs in new clothes/formulations to extend product life-cycles or worrying about once-a-day versus twice-a-day pills. This belief is encapsulated in the mantra ‘The End of the Age of Incrementalism’ that can be heard in the halls of RNAi Therapeutics companies and fits well into an increasingly risk-averse regulatory environment that further emphasizes more and more comparative effectiveness during the drug approval process.

That this belief is also gaining acceptance in Big Pharma was recently highlighted by GSK’s decision to exit pain and depression and instead focus on developing life-altering drugs for orphan diseases where the RNAi Therapeutics platform should have a competitive edge. GSK’s decision was somewhat surprising given that they had a drug under active review with the FDA for restless legs syndrome (RLS) and that with the right marketing could have come close to blockbuster sales. RLS is a disease that has long struggled to gain acceptance within the medical community and has often been ridiculed as a phantom disease. Nevertheless, there has been some commercial success, not least through GSK’s own efforts. With the life-cycle of its original RLS drug coming to an end, it struck a partnership with Xenoport for a gabapentin pro-drug, an oral small molecule by the name of Horizant (XN13512), that has met all the pre-specified primary and secondary end-points in all 4 phase III trials. This made the author of this blog believe that it should be a smooth approval process if there ever was one.

Gabapentin has long been used for epilepsy and some forms of pain. Rather than developing gabapentin itself for RLS, GSK and Xenoport instead chose the pro-drug version which was designed to be taken up through a different mechanism in the gut, arguing that the changed pharmacology would make for a superior drug. I suspect, however, that the fact that the pro-drug, unlike gabapentin itself, had a long period of patent protection ahead played no minor role in this choice.

Well, this strategy just came back to bite them (and investors) and GSK must have seen it coming [update 2/18/10: Per Xenoport's conference call, the complete response letter was the first time the rat carcinogenicity were brought to the companies' attention by the FDA]: The FDA rejected the drug because rat carcinogenicity studies showed a drug-related increase in a form of pancreatic cancer. The FDA further stated that although it had known for a long time that gabapentin was associated with such a risk, the risk was justified for a condition like epilepsy, but not RLS. Clearly, the FDA was not impressed by a drug that one might argue had largely been developed for its patent profile and for a condition that is not really considered life-threatening. Looking at the RNAi Therapeutics pipeline, chances are low that the FDA will pull similar rabbits out of its hat (see footnote *) for drugs aiming to treat solid cancer, severe hypercholesterolemia, and graft-associated morbidities and mortalities, and should only make the next Big Pharma-RNAi Therapeutics deal come one step closer.

* The reason for characterizing the FDA’s decision this way is two-fold. Firstly, the FDA has known, and even stated as much in its complete response letter, that gabapentin had been known to be associated with pancreatic cancer in male rats. The question arises why the FDA has not told Xenoport from the outset, in their initial meetings, that it won’t accept a gabapentin-based drug for RLS for this reason. Of course, the companies share some of the responsibility for this lack of foresight costing them and investors years and hundreds of millions $$$. Secondly, the pre-clinical carcinogenicity studies are of questionable value now that the experience of gabapentin in humans has, to my knowledge, not been associated with cancer and increasingly looks to be a sex and species-specific phenomenon.